We propose to conduct a case-series study in men and women with lung cancer, investigating molecular markers of susceptibility, biologically effective dose, and tumor tissue alterations. These markers will be evaluated in relation to exposure data on active and passive smoke exposure, occupational exposures and reproductive and hormonal factors, in order to elucidate reasons for the increase in lung cancer, particularly adenocarcinoma, in both smoking and non-smoking women. To optimize our capabilities to enroll nonsmokers with lung cancer, we will work with the Lung Committee investigators of the Southwest Oncology Group and collaborating members of the NCI lung intergroup to identify large numbers of patients with lung cancer, enrolling 120 never-smoking women with lung cancer and an equal number of males, as well as 200 each of ever smoking females and males. We have two primary hypotheses: that women are at higher risk due to susceptibility to tobacco-smoke carcinogens, based on metabolic variability. We propose that markers of the interactions of environmental and genetic risk factors for lung cancer (DNA adducts), as well as genetic alterations in tumor tissue (p53 and kras mutations), will reflect differences in exposures and susceptibility between men and women, smokers and non-smokers, and will elucidate the disproportionate variability in risk by gender and smoking status. Our second hypothesis is that steroid hormones, which appear to play a role in lung carcinogeneis, will have a greater effect in women than in men and in never smokers rather than smokers. We predict that tumor HER2 amplification and estrogen receptors will vary by gender and smoking status, particularly in relation to environmental and genetic (SNPs in carcinogen and steroid hormone metabolism pathways) risk factors. Biomarkers of exposure, susceptibility, and effect will be assayed in the blood and tumor tissue of these women men with lung cancer and evaluated in relation to questionnaire data to test the proposed hypotheses. Results from this study, the largest to date to evaluate biomarkers of susceptibility and effect, will likely elucidate reasons for the rise in lung cancer, particularly adenocarcinomas, in smoking and non-smoking women.